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T0070907

Human PPARγ antagonist,potent and selective CAS# 313516-66-4

T0070907

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Chemical structure

T0070907

3D structure

Chemical Properties of T0070907

Cas No. 313516-66-4 SDF Download SDF
PubChem ID 2777391 Appearance Powder
Formula C12H8ClN3O3 M.Wt 277.66
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 10 mg/mL (36.02 mM; Need ultrasonic)
Chemical Name 2-chloro-5-nitro-N-pyridin-4-ylbenzamide
SMILES C1=CC(=C(C=C1[N+](=O)[O-])C(=O)NC2=CC=NC=C2)Cl
Standard InChIKey FRPJSHKMZHWJBE-UHFFFAOYSA-N
Standard InChI InChI=1S/C12H8ClN3O3/c13-11-2-1-9(16(18)19)7-10(11)12(17)15-8-3-5-14-6-4-8/h1-7H,(H,14,15,17)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of T0070907

DescriptionPotent and selective PPARγ antagonist (IC50 = 1 nM). Displays > 800-fold selectivity for PPARγ over PPARα and PPARδ. Blocks transcriptional activity of PPARγ in vitro and inhibits rosiglitazone-induced adipogenesis.

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Preparing Stock Solutions of T0070907

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.6015 mL 18.0076 mL 36.0153 mL 72.0305 mL 90.0382 mL
5 mM 0.7203 mL 3.6015 mL 7.2031 mL 14.4061 mL 18.0076 mL
10 mM 0.3602 mL 1.8008 mL 3.6015 mL 7.2031 mL 9.0038 mL
50 mM 0.072 mL 0.3602 mL 0.7203 mL 1.4406 mL 1.8008 mL
100 mM 0.036 mL 0.1801 mL 0.3602 mL 0.7203 mL 0.9004 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on T0070907

T0070907 is a selective antagonist of peroxisome proliferator-activated receptor γ (PPARγ) with IC50 value of 1nM [1].

T0070907 shows high affinity to PPARγ with Ki of 1nM. The Ki values of it to PPARα and PPARδ are 0.85 and 1.8μM, respectively, demonstrating the high selectivity of T0070907. It is found that T0070907 binds PPARγ within the cysteine 313 in helix 3 of human PPARγ2, subsequently blocks PPARγ function. In transient transfection assay, T0070907 inhibits the transactivation of PPARγ in the presence of rosiglitazone (a PPARγ agonist) with IC50 value in the nM range. T0070907 can block the induction of adipogenesis of the adipogenic cell line 3T3-L1. Additionally, T0070907 is found to suppress the interaction between PPARγ and the coactivator derived peptide, while promoting the recruitment of the NCoR-derived peptide to PPARγ. Furthermore, T0070907 can also promote a significant increase in the recruitment of NCoR to the PPARγ/RXRα heterodimer [1].

References:
[1] Lee G, Elwood F, McNally J, Weiszmann J, Lindstrom M, Amaral K, Nakamura M, Miao S, Cao P, Learned RM, Chen JL, Li Y. T0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities. J Biol Chem. 2002 May 31;277(22):19649-57.

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References on T0070907

T0070907, a PPAR gamma inhibitor, induced G2/M arrest enhances the effect of radiation in human cervical cancer cells through mitotic catastrophe.[Pubmed:24642720]

Reprod Sci. 2014 Nov;21(11):1352-61.

Overexpression of peroxisome proliferator activator receptor gamma (PPARgamma) has been implicated in many types of cancer including cervical cancer. Radiation therapy remains the main nonsurgical modality for the treatment of cervical cancer. The present study reports the impact of pharmacological inhibition of PPARgamma in enhancing the radiosensitization of cervical cancer cells in vitro. Three cervical cancer cell lines (HeLa, SiHa, and Me180) were treated with a PPARgamma inhibitor, T0070907, and/or radiation. The changes in protein, cell cycle, DNA content, apoptosis, and cell survival were analyzed. The PPARgamma is differentially expressed in cervical cancer cells with maximum expression in ME180 cells. T0070907 has significantly decreased the tubulin levels in a time-dependent manner in ME180 cells. The decrease in the tubulin levels after T0070907 in ME180 and SiHa cells was associated with significant increase in the cells at the G2/M phase. The changes in the tubulin and G2/M phase were not evident in HeLa cells. T0070907 reduced the protein levels of PPARgamma; however, PPARgamma silencing had no effect on the alpha-tubulin level in ME180 cells suggesting the PPARgamma-dependent and -independent actions of T0070907. To ascertain the impact of synergistic effect of T0070907 and radiation, HeLa and ME180 cells were pretreated with T0070907 and subjected to radiation (4 Gy). Annexin V-fluorescein isothiocyanate analysis revealed increased apoptosis in cells treated with radiation and T0070907 when compared to control and individual treatment. In addition, T0070907 pretreatment enhanced radiation-induced tetraploidization reinforcing the additive effect of T0070907. Confocal analysis of tubulin confirmed the onset of mitotic catastrophe in cells treated with T0070907 and radiation. These results strongly suggest the radiosensitizing effects of T0070907 through G2/M arrest and mitotic catastrophe.

T0070907 inhibits repair of radiation-induced DNA damage by targeting RAD51.[Pubmed:27544453]

Toxicol In Vitro. 2016 Dec;37:1-8.

T0070907 (T007), a PPARgamma inhibitor, can reduce alpha and beta tubulin proteins in some cancer cell lines. Thus, T007 has been suggested as an antimicrotubule drug. We previously reported that T007 increased radiosensitivity by inducing mitotic catastrophe in cervical cancer cells. In this study, we investigated the underlying mechanisms of the T007-mediated increase in radiosensitivity. T007 pre-treatment attenuated RAD51 protein levels and ionising radiation (IR)-induced nuclear foci formation, resulting in more frequent centrosome amplification and multipolar mitotic spindle formation in cervical cancer cells. Furthermore, T007 pre-treatment delayed the clearance of IR-induced gamma-H2AX and increased radiosensitivity in cervical cancer cells. In contrast, none of these changes were observed in normal cells. Our data demonstrate for the first time that T007 impairs the repair of IR-induced DNA double-strand breaks by inhibiting RAD51, a key protein in homologous recombination repair, increases IR-induced mitotic catastrophe, and leads to increased death of IR-treated cells. These findings support T007 as a potential RAD51 inhibitor to increase tumour response to radiation therapy.

Peroxisome proliferator-activated receptor gamma (PPARgamma)-independent specific cytotoxicity against immature adipocytes induced by PPARgamma antagonist T0070907.[Pubmed:23995653]

Biol Pharm Bull. 2013;36(9):1428-34.

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays indispensable roles in adipogenesis, which is frequently impaired under pathological conditions such as non-alcoholic steatohepatitis (NASH). Thus, a potent PPARgamma antagonist, T0070907 is known as a useful tool for understanding such pathological conditions, while T007097 was also suggested to have PPARgamma-independent actions. In the present study, we found that T0070907 inhibited adipogenesis concomitantly with the induction of rapid apoptosis of immature adipocytes within 2 h, whereas another PPARgamma antagonist, SR-202 did not show such cytotoxicity. However, T0070907 did not affect the viabilities of pre-adipocytes, mature adipocytes, and NIH-3T3 fibroblasts. The cytotoxic effect of T0070907 was not inhibited by GW1929, a PPARgamma agonist, but was inhibited by alpha-tocopherol, which was previously shown to provide clinical benefit to NASH patients. Interestingly, treatment with high amounts of alpha-tocopherol alone slightly increased the cellular lipid content in mature adipocytes, but did not affect PPARgamma-dependent luciferase reporter expression in COS-7 cells. Moreover, other lipophilic antioxidants, such as tocotrienols, tert-butylhydroquinone, and butylated hydroxyanisole, also inhibited T0070907-induced apoptosis like alpha-tocopherol. Consequently, it is suggested that T0070907 efficiently inhibits adipogenesis, not only via PPARgamma-dependent manner, but also through the induction of apoptosis specifically against immature adipocytes via oxidative stress in a PPARgamma-independent manner.

Peroxisome proliferator-activated receptor gamma inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular carcinoma cells.[Pubmed:15781638]

Cancer Res. 2005 Mar 15;65(6):2251-9.

Activation of the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits growth and survival of hepatocellular carcinoma (HCC) cell lines. To further investigate the function of PPARgamma in HCC, PPARgamma expression patterns in primary tumors were examined, and the responses of two HCC cell lines to PPARgamma activation and inhibition were compared. PPARgamma expression was increased in HCC and benign-appearing peritumoral hepatocytes compared with remote benign hepatocytes. Both compound PPARgamma inhibitors and PPARgamma small interfering RNAs prevented HCC cell lines from adhering to the extracellular matrix. Loss of adhesion was followed by caspase-dependent apoptosis (anoikis). PPARgamma inhibitors had no effect on initial beta1 integrin-mediated adhesion, or on total focal adhesion kinase levels but did reduce focal adhesion kinase phosphorylation. The PPARgamma inhibitor T0070907 was significantly more efficient at causing cancer cell death than the activators troglitazone and rosiglitazone. T0070907 caused cell death by reducing adhesion and inducing anoikis, whereas the activators had no direct effect on adhesion and caused cell death at much higher concentrations. In conclusion, PPARgamma overexpression is present in HCC. Inhibition of PPARgamma function causes HCC cell death by preventing adhesion and inducing anoikis-mediated apoptosis. PPARgamma inhibitors represent a potential novel treatment approach to HCC.

A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes.[Pubmed:15284281]

J Pharmacol Exp Ther. 2004 Nov;311(2):683-90.

Arachidonyl ethanolamine, which is commonly known as anandamide, was the first endogenous compound to be identified that binds to the cannabinoid receptors. Anandamide mimics many of the physiological effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), including hypothermia, antinociception, immobility, catalepsy, and immune modulation. In the present studies, we show that anandamide caused a concentration-dependent inhibition of interleukin-2 in primary splenocytes. The CB1 and CB2 antagonists, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-H-pyrazole- 3 carboxyamidehydrochloride] and SR144528 [N-[(1S)-endo-1,3,3,-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphen yl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide], when used in combination, did not antagonize the inhibition of interleukin-2 by anandamide. Additionally, neither UCM707 [N-(3-furanylmethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide], the inhibitor of the putative anandamide membrane transporter (AMT), nor methyl arachidonoyl fluorophosphonate (MAFP), the inhibitor of fatty acid amidohydrolase (FAAH), were able to affect the inhibitory activity of anandamide upon interleukin-2. Interestingly, arachidonic acid caused a concentration-dependent inhibition of interleukin-2 secretion (IC(50) = 10.3 microM), which was similar to that of structurally related anandamide (IC(50) = 11.4 microM). The inhibition of interleukin-2 by anandamide and arachidonic acid was partially reversed by pretreatment with the nonspecific cyclooxygenase inhibitors, flurbiprofen and piroxicam. Moreover, NS398 [N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide], a cyclooxygenase-2-specific inhibitor, also attenuated the inhibitory effects of anandamide and arachidonic acid upon interleukin-2 secretion. Finally, pretreatment with a peroxisome proliferator-activated receptor gamma (PPARgamma)-specific antagonist, T0070907 [2-chloro-5-nitro-N-4-pyridinyl-benzamide], partially antagonized anandamide-mediated suppression of IL-2 secretion. Collectively, the aforementioned studies suggest that inhibition of interleukin-2 secretion by anandamide is independent of CB1/CB2 and the AMT/FAAH system. Additionally, these studies also suggest that inhibition of interleukin-2 is mediated by a PPARgamma, which is activated by a cyclooxygenase-2 metabolite of anandamide.

T0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities.[Pubmed:11877444]

J Biol Chem. 2002 May 31;277(22):19649-57.

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma (NR1C3)) plays a central role in adipogenesis and is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. In a search for novel non-TZD ligands for PPARgamma, T0070907 was identified as a potent and selective PPARgamma antagonist. With an apparent binding affinity (concentration at 50% inhibition of [(3)H]rosiglitazone binding or IC(50)) of 1 nm, T0070907 covalently modifies PPARgamma on cysteine 313 in helix 3 of human PPARgamma2. T0070907 blocked PPARgamma function in both cell-based reporter gene and adipocyte differentiation assays. Consistent with its role as an antagonist of PPARgamma, T0070907 blocked agonist-induced recruitment of coactivator-derived peptides to PPARgamma in a homogeneous time-resolved fluorescence-based assay and promoted recruitment of the transcriptional corepressor NCoR to PPARgamma in both glutathione S-transferase pull-down assays and a PPARgamma/retinoid X receptor (RXR) alpha-dependent gel shift assay. Studies with mutant receptors suggest that T0070907 modulates the interaction of PPARgamma with these cofactor proteins by affecting the conformation of helix 12 of the PPARgamma ligand-binding domain. Interestingly, whereas the T0070907-induced NCoR recruitment to PPARgamma/RXRalpha heterodimer can be almost completely reversed by the simultaneous treatment with RXRalpha agonist LGD1069, T0070907 treatment has only modest effects on LGD1069-induced coactivator recruitment to the PPARgamma/RXRalpha heterodimer. These results suggest that the activity of PPARgamma antagonists can be modulated by the availability and concentration of RXR agonists. T0070907 is a novel tool for the study of PPARgamma/RXRalpha heterodimer function.

Description

T0070907 is a potent PPARγ antagonist with a Ki of 1 nM.

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